|Publication number||US6521223 B1|
|Application number||US 09/503,544|
|Publication date||18 Feb 2003|
|Filing date||14 Feb 2000|
|Priority date||14 Feb 2000|
|Also published as||CA2398935A1, EP1263793A1, WO2001060868A1|
|Publication number||09503544, 503544, US 6521223 B1, US 6521223B1, US-B1-6521223, US6521223 B1, US6521223B1|
|Inventors||Pericles Calias, Robert J. Miller|
|Original Assignee||Genzyme Corporation|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (34), Non-Patent Citations (6), Referenced by (69), Classifications (24), Legal Events (4)|
|External Links: USPTO, USPTO Assignment, Espacenet|
Throughout this application, various publications are referenced. All publications referenced herein, including published patent applications and issued or granted patents, are hereby incorporated by reference in their entireties into this application.
This invention relates to single phase gel products formed by the reaction of a polyanionic polysaccharide and divinyl sulfone (“DVS”), and preferably formed by the reaction of hyaluronic acid (“HA”) and divinyl sulfone. The single phase gel products of this invention are particularly useful for preventing the formation of adhesions between affected tissue surfaces of a subject who has undergone a surgical procedure.
Adhesion formation is a well known complication of many types of surgical procedures, and particularly abdominal and bowel surgeries. Adhesion formation typically occurs as a result of the formation of a fibrin clot which transforms into scar tissue connecting different tissues which are normally separated. Surgical intervention is frequently required in order to eliminate the adhesions, although the adhesions can, and often do, reappear following the surgery. The primary objective of adhesion prevention formulations is to interrupt the adhesion formation mechanism, which is believed to result from the diffusion of fibrinogen into the space between the tissues subject to surgical trauma, thereby causing the formation of fibrin clots in the space.
In addition to acting as an adhesion barrier, a successful anti-adhesion formulation should be “biocompatible”, meaning that it has no medically unacceptable toxic or injurious effects on the biological function of the subject, and “bioabsorbable”, meaning that it can be absorbed by the tissue without remaining in the subject as an implant device. Thus, the formulation should remain in the body for a sufficient period of time to be effective in separating the tissue and preventing adhesions, while being absorbed by the tissue once the danger of adhesion formation has ended, thereby minimizing any long term effects which may result from the use of an implant device.
Hyaluronic acid (“HA”) is a naturally occurring mucopolysaccharide found, for example, in synovial fluid, in vitreous humor, in blood vessel walls, the umbilical cord, and in other connective tissues. The polysaccharide consists of alternating N-acetyl-D-glucosamine and D-glucuronic acid residues joined by alternating β1-3 glucoronidic and β1-4 glucosaminidic bonds, so that the repeating unit is —(1→4)-β-D-G1cA-(1→3)-βD-G1cNAc-. In water, hyaluronic acid dissolves to form a highly viscous fluid. The molecular weight of hyaluronic acid isolated from natural sources generally falls within the range of from about 5×104 up to about 1×107 daltons.
Hyaluronic acid, in chemically modified form, is known to be useful as a surgical aid to prevent adhesions and accretions of body tissues during the post-operation period. The chemically modified hyaluronic acid gel or film is injected or inserted into the locus between the tissues that are to be kept separate to inhibit their mutual adhesion. Chemically modified hyaluronic acid can also be useful for controlled release drug delivery. See U.S. Pat. No. 4,937,270 and U.S. Pat. No. 5,017,229, which disclose chemically modified versions of HA, or HA in combination with other polyanionic polysaccharides, such as carboxymethylcellulose, which are prepared by reacting the HA with a carbodiimide. The chemically modified version of HA and carboxymethylcellulose is commercially available in film form as Seprafilm® membranes from the Genzyme Corporation.
I. Danishefsky et al., Carbohydrate Res., Vol. 16, pages 199-205, 1971, describe the modification of a mucopolysaccharide by converting the carboxyl groups of the mucopolysaccharide into substituted amides by reacting the mucopolysaccharide with an amino acid ester in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (“EDC”) in aqueous solution. Danishefsky et al. react glycine methyl ester with a variety of polysaccharides, including HA. The resulting products are water soluble; that is, they rapidly disperse in water or in an aqueous environment such as is encountered between body tissues.
Proposals for rendering HA compositions less water soluble include cross-linking the HA. R. V. Sparer et al., 1983, Chapter 6, pages 107-119, in T. J. Roseman et al., Controlled Release Delivery Systems, Marcel Dekker, Inc., New York, describe modifying HA by attaching cysteine residues to the HA by amide bonds, and then cross-linking the cysteine-modified HA by forming disulfide bonds between the attached cysteine residues.
U.S. Pat. No. 5,676,964 describes the preparation of cross-linked polysaccharides, including HA, wherein the cross-linking reaction occurs as a result of covalent bonds formed between carboxyl groups and hydroxyl groups of adjacent polysaccharide molecules.
U.S. Pat. No. 4,582,865; U.S. Pat. No. 4,636,524 and U.S. Pat. No. 5,128,326 describe HA compositions in which the HA is cross-linked by reaction with divinyl sulfone, and further describe the use of these compositions for drug delivery applications. U.S. Pat. No. 4,605,691 describes a method for preparing cross-linked HA compositions using divinyl sulfone as a cross-linking agent in an alkali solution.
U.S. Pat. No. 5,143,724; U.S. Pat. No. 5,247,698 and U.S. Pat. No. 5,399,351 disclose biocompatible, viscoelastic polymeric gel slurries prepared by reacting hyaluronic acid and a cross-linking agent such as divinyl sulfone, which are used in anti-adhesion formulations. The gel slurry is a two phase composition comprising discrete particles distributed in a polymer solution. In one embodiment, the slurry is formed from cross-linked hyaluronic acid particles contained in a solution of hyaluronic acid. The two phase slurries are believed to be effective in preventing adhesion formation due to their ability to separate affected tissue surfaces coupled with the ability to restrict diffusion at the site of potential adhesion formation.
U.S. Pat. No. 5,783,691 relates to hyaluronic acid compositions which are prepared by crosslinking hyaluronic acid with a phosphorus-containing reagent, such as sodium phosphate, in an alkaline medium to form a gel product. The crosslinking reagents described in this patent are not completely soluble, resulting in a two phase system, with one phase containing the crosslinked product. The gels can contain drugs and can be used as drug release vehicles upon administration to a subject.
Two phase gel slurries do suffer from certain drawbacks, however. For instance, the material must be processed correctly in order to improve the handling properties of the material, and to permit its therapeutic application through the narrow openings of needles and other applicators, particularly for minimally invasive surgical indications. Such processing requires the use of processing equipment and the application of shear forces to the material, which in turn can result in a decrease in viscosity (thinning). Two phase materials contain dispersed, heterogeneous particles which tend to plug the narrow openings of such delivery systems. A single phase, homogeneous composition is more useful in minimally invasive surgical applications where devices are introduced into the body through narrow access ports.
It would therefore be highly desirable to formulate a single phase gel solution which is capable of preventing the formation of adhesions, and which can be easily handled and stored for future use, and which possesses the advantageous characteristics of two phase gels.
The present invention features a cross-linked polyanionic composition which is useful for the prevention of adhesions which can arise as the result of a surgical procedure performed on a subject. The cross-linked composition is prepared by the reaction of the polyanionic polysaccharide with divinyl sulfone. The reaction occurs in an aqueous solution and results in the formation of a gel. The gel solution is neutralized, preferably by acidifying the solution, and a solid is precipitated from the solution. The solid can be pulverized to form a powder, and subsequently rehydrated with water to form a single phase, purified gel having properties suitable for use in anti-adhesion formulations.
In one embodiment, the invention features a method for preparing a single phase gel for use in preventing the formation of surgical adhesions. The gels of this invention are prepared by reacting a polyanionic polysaccharide with divinyl sulfone to form a cross-linked gel. Preferably, the polyanionic polysaccharide is hyaluronic acid or carboxymethyl cellulose, and the molar ratio of divinyl sulfone to polyanionic polysaccharide is from about 0.1:1 to about 1: 1, and more preferably from about 0.2:1 to about 0.6:1. The gel is neutralized by the addition of an acidic compound, such as an inorganic acid, typically hydrochloric acid or sulfuric acid, to an aqueous solution of the gel and the cross-linking agent. The gel can be precipitated as a solid, preferably as a powder or fine particles, and stored until it is desired to reconstitute the gel by rehydration of the powder.
Terminal sterilization of the gel can be accomplished by autoclaving the gel, and this procedure does not have any substantial adverse impact on the gel structure. Terminal sterilization is a cost effective method for manufacturing a medical device since it can assure a lower bioburden than aseptic processing, and thereby reduces the risk of infection. Typically, terminal sterilization involves steam autoclaving of aqueous preparations, and either ethylene oxide treatment or high energy bombardment (irradiation or E beam treatment) of the material in solid or dry form.
In one aspect of this embodiment, the properties of the gel are modified by subjecting the gel to heat treatment at a temperature in the range of from about 100° C. to about 150° C. Heat treatment has the effect of modifying the properties of the gel, such as its viscosity. The effect of the heat treatment on specific polymers is generally not predictable in advance, and is based on such factors as the relative degree of cross-linking. Heat treatment of a gel material can be employed to alter the final viscosity of the gel by either causing more polymer to dissolve in solution, which tends to increase the viscosity, or by reducing the molecular weight of the polymer, which tends to reduce the viscosity. Thus, adjustments to the gel viscosity can be easily carried out using this approach.
In another embodiment, the invention features a method for preventing the formation of adhesions by applying the cross-linked gel prepared according to the method of this invention to the surface of the tissue which is exposed during a surgical procedure and which is in proximity to the site of the procedure.
The composition can be advantageously applied to the tissue surfaces using non-invasive means, such as by means of endoscopic instruments. Minimally invasive surgical techniques are less traumatic to the patient, more cosmetically appealing, allow faster recovery times, and have lower risks of infection. The alternative to endoscopic surgery is an open surgical procedure, such as laparotomy, involving long incision lines and the risk of infection.
Sufficient material should be used to separate the tissue surfaces that may potentially develop adhesions. The gels of this invention remain in place for at least about 7 days, but no more than about 30 days, which is a sufficient period of time to prevent the formation of the adhesions. The gels of this invention are bioabsorbable, and are not toxic or injurious to the patient. These gels are also water-insoluble, due to the cross-linking, which enables the gels to remain in the body without being immediately absorbed.
In a further embodiment, a drug substance may be incorporated in the gel for delivery to the tissue at the site of the surgery. Such drug substances include, for instance, NSAIDS, lidocaine, and derivatives thereof, steroids, growth factors, cytokines, antibiotics, etc., and the like.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Unless mentioned otherwise, the techniques employed or contemplated herein are standard methodologies well known to one of ordinary skill in the art. The materials, methods and examples are illustrative only, and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the appended claims.
The present invention provides a method for preparing a water insoluble biocompatible composition comprising reacting a polyanionic polysaccharide with divinyl sulfone in an aqueous solution to form a gel, neutralizing the pH of the solution, and precipitating a solid from the solution. The polyanionic polysaccharide used may be selected from the group consisting of hyaluronic acid, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, carboxymethylcellulose, carboxymethyl amylose and a mixture of hyaluronic acid and carboxymethylcellulose. In one embodiment of the invention, the solid precipitated from the solution is then rehydrated to form a gel. The invention further provides that the rehydrated gel may then be subjected to heat treatment. In one embodiment, the rehydrated gel is heated to a temperature in the range from about 100° C. to about 150° C.
The present invention also provides a method for preparing a water insoluble biocompatible composition comprising reacting a polyanionic polysaccharide with divinyl sulfone in an aqueous solution to form a gel, neutralizing the pH of the solution, and precipitating a solid from the solution wherein the polyanionic polysaccharide is hyaluronic acid. In one embodiment, the molar ratio of divinyl sulfone:hyaluronic acid is from about 0.1:1 to about 1:1. In another embodiment, the molar ratio of divinyl sulfone:hyaluronic acid is from about 0.2:1 to about 0.6:1.
The present invention also provides for a single phase gel product formed by any of the methods of the invention herein described. The single phase gel product of the invention may be sterilized. The single phase gel product of the invention may further comprise a drug.
The present invention also provides for a method for the prevention of adhesions in a subject comprising applying the gel product of the invention to a region between two tissue surfaces to be separated during the healing process following surgery. The subject may be a human patient.
Additionally, the surgery being performed on the subject may be one selected from the group consisting of abdominal surgery, pelvic surgery, gynecological surgery, orthopedic surgery, and cardiac surgery.
As used herein, and unless otherwise indicated, the term “polyanionic polysaccharide” denotes a polysaccharide containing more than one negatively charged group, e.g., carboxyl groups at pH values above about pH 4.0. This includes hyaluronic acid (“HA”), any of its hyaluronate salts, including, for example, sodium hyaluronate (the sodium salt), potassium hyaluronate, magnesium hyaluronate, and calcium hyaluronate, carboxymethylcellulose (“CMC”), and mixtures of hyaluronic acid and carboxymethylcellulose, and carboxymethyl amylose.
A “biocompatible” substance, as the term may be used herein, is one that has no medically unacceptable toxic or injurious effects on biological function.
A “bioabsorbable” substance is one which is maintained in the body in a relatively intact form for at least about 7 days, and is then completely absorbed by the body after about 30 days thereafter. A bioabsorbable substance is thus not considered to be an “implant”, which remains in the body for more than about 30 days without decomposition. A bioabsorbable substance does not have to meet the more stringent is FDA requirement imposed on implants.
A “cross-linked polyanionic polysaccharide” is a polyanionic polysaccharide which has been reacted with a divinyl sulfone cross-linking agent to form a 3-dimensional network by covalent bonding between the divinyl sulfone and reactive sites on adjacent polymers. The degree of cross-linking can be measured by the amount of cross-linking agent consumed in the cross-linking reaction.
The expression “preventing adhesion formation” is intended to encompass not only the complete elimination of adhesions, but the substantial reduction in the amount or number of adhesions formed as compared to the amount or number of adhesions formed using a control substance such as saline, or the absence of any treatment to reduce the level of adhesions.
A “gel” is a colloidal suspension of a dispersed solid phase in a continuous phase. In the context of this invention, the dispersed solid phase comprises particles of a polyanionic polysaccharide, and the continuous phase is water. A “water soluble” gel, as that term is used herein, is a gel which as an aqueous 1% weight/weight (“w/w”) solution of the cross-linked polyanionic polysaccharide gel, when placed in a 50 mL beaker of distilled water maintained at about 20° C., and allowed to stand without stirring, dissolves completely into a single phase within 20 minutes. A “water insoluble” gel is a gel which, when prepared under the conditions as described for a water soluble gel, is structurally intact after 20 minutes. The gels of the present invention are water insoluble, enabling them to function as effective adhesion reduction devices.
A solution is “neutralized” when the pH value of the solution is adjusted so that the final pH of the solution is approximately 7.0, or alternatively, in the range of from about 6.0 to about 8.0. The relatively alkaline solutions of the present invention are adjusted by lowering the pH by the addition of an acidic compound to the reaction mixture of the polyanionic polysaccharide and divinyl sulfone.
The anti-adhesion formulations of this invention can be prepared from a polyanionic polysaccharide which is cross-linked by reaction with divinyl sulfone. The reactants can be dissolved in water at a basic pH, preferably at a pH of about 12, and the reaction is allowed to proceed until a gel is formed. The mode of addition of the reagents is not critical to the reaction.
The amount of divinyl sulfone consumed in the cross-linking reaction generally varies from about 0.1 moles of DVS up to 1.0 mole of DVS per mole of polyanionic polysaccharide. Lower amounts of DVS produce lightly cross-linked gels which tend to be more soluble, while higher amounts of DVS produce more tightly cross-linked gels which tend to be more insoluble.
The preferred polyanionic polysaccharides are hyaluronic acid and carboxymethyl cellulose. Hyaluronic acid, or its salts such as sodium hyaluronate, is readily soluble in water. HA from any of a variety of sources can be used. For instance, HA can be extracted from animal tissues, such as rooster combs, or harvested as a product of bacterial fermentation. HA can be produced in commercial quantities using bioprocess technology, as described for example in PCT Publication No. WO 86/04355.
The product formed from the reaction of HA and DVS is then mixed with water, and the pH of the mixture is adjusted to an approximately neutral level, e.g. about 7.0, or from about 6.0 to about 8.0, by the addition of an acidic compound to the solution. Suitable acids include sulfuric acid and hydrochloric acid.
The gel is then precipitated with ethanol as a solid. Preferably, the gel is pulverized to form a powder, which can be stored until it is needed for medical use. The powder can be easily reconstituted by rehydration, and optionally subjected to heat treatment to adjust the rheological properties to achieve the desired physical characteristics.
From the above description, one skilled in the art can readily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope of thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
As one skilled in the art will appreciate, the gels of this invention can be made using methods which may differ in certain particulars from those methods exemplified herein. For example, when precipitating the solid from solution, any water miscible solvent having a lower polarity than water may be used. Suitable solvents include, for example, ethanol, isopropyl alcohol and acetone.
The following examples of the invention are provided by way of illustration only, and are not intended to limit the invention as set forth in the appended claims.
200 mL of a 0.2 N sodium hydroxide solution was added to 8.0 grams of hyaluronic acid (19.95 mmol), and the mixture was stirred at room temperature until it fully dissolved (about 3 hours). 266 mL of divinyl sulfone (4.0 mmol) was added to the hyaluronic acid solution and vigorously stirred for about one minute. The reaction mixture was allowed to stand at room temperature for one hour. The resulting gel was placed in D.I. water for 24 hours, and then chopped into quarters, and allowed to stand in PBS for an additional 24 hours. 5 mL of PBS was added to the swollen gel, and the mixture was mixed under high sheer conditions. The pH of the solution was then adjusted to 7.2 with 6 N hydrochloric acid, followed by precipitation with absolute ethanol (3.0 L). The white precipitate was collected and dried under vacuum. The powder is easily rehydrated upon the addition of PBS and high shear mixing.
Following this procedure, hyaluronic acid gels can be synthesized with varying amounts of divinyl sulfone and reconstituted at different concentrations (expressed as % solid per volume, where 1% equals 1 gram/100 mL) to obtain a desired Theological property. The results are shown in Tables I, II and III below for gels having DVS:HA molar ratios of 0.2:1, 0.3:1 and 0.6:1, respectively, before and after heat treatment at 121° C. for 20 minutes, where the numbers in parentheses indicate the values before heat treatment.
DVS:HA Mole Ratio of 0.2:1
DVS:HA Mole Ratio of 0.3:1
DVS:HA Mole Ratio of 0.6:1
The Tables above show that the gels become more resistant to degradation by heat as the amount of cross-linking is increased. The gels made using a 0.6:1 DVS:HA molar ratio are quite stable to heat treatment, which directly correlates to the stability of the gels under autoclave conditions.
200 mL of a 0.2 N sodium hydroxide solution was added to 8.0 grams of hyaluronic acid (19.95 mmol), and the mixture was stirred at room temperature until it fully dissolved (about 3 hours). 396 mL of divinyl sulfone (5.99 mmol) was added to the hyaluronic acid solution and vigorously stirred for about one minute. The reaction mixture was allowed to stand at room temperature for one hour. The resulting gel was placed in D.I. water for 24 hours, and then chopped into quarters, and allowed to stand in PBS for an additional 24 hours. 5 mL of PBS was added to the swollen gel, and the mixture was mixed under high sheer conditions. The pH of the solution was then adjusted to 7.2 with 6 N hydrochloric acid, followed by precipitation with absolute ethanol (3.0 L). The white precipitate was collected and dried under vacuum. The powder is easily rehydrated upon the addition of PBS and high shear mixing.
200 mL of a 0.2 N sodium hydroxide solution was added to 8.0 grams of hyaluronic acid (19.95 mmol), and the mixture was stirred at room temperature until it fully dissolved (about 3 hours). 798 mL of divinyl sulfone (12.0 mmol) was added to the hyaluronic acid solution and vigorously stirred for about one minute. The reaction mixture was allowed to stand at room temperature for one hour. The resulting gel was placed in D.I. water for 24 hours, and then chopped into quarters, and allowed to stand in PBS for an additional 24 hours. 5 mL of PBS was added to the swollen gel, and the mixture was mixed under high sheer conditions. The pH of the solution was then adjusted to 7.2 with 6 N hydrochloric acid, followed by precipitation with absolute ethanol (3.0 L). The white precipitate was collected and dried under vacuum. The powder is easily rehydrated upon the addition of PBS and high shear mixing.
Gels prepared from the rehydrated powder as shown in Example 1 were tested for efficacy in preventing post-operative adhesions in a rat cecal abrasion model as described in Burns et al., Eur. J. Surg. 1997, Suppl. 577, 40-48. Ten (10) rats were used in each study. Group 1 used a gel having a concentration of 1.5% of active ingredient, and Group 2 used a gel having a concentration of 2.5% of active ingredient. The results are shown in Table IV below listed as the percentage of each group with adhesions of grade greater than 2; the average incidence of adhesions, plus or minus the standard error of the mean; and the percentage of each group with no adhesions.
% w/ adh. ≧ 2
Avg. Inc. ± SEM
% w/ no adh.
1.5 ± 0.4
0.6 ± 0.3
0.2 ± 0.1
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3106439||13 Jan 1960||8 Oct 1963||Tootal Broadhurst Lee Co Ltd||Process of dry creaseproofing cellulosic fabrics with divinyl shlphone|
|US3316308||16 Apr 1964||25 Apr 1967||Welch Clark M||Polymeric adducts of divinyl sulfone with water and preparation thereof|
|US3357784||30 Sep 1964||12 Dec 1967||Kendall & Co||Exposure to intense ultraviolet light to improve characteristics of cellulosic fabrics in divinyl sulfone and glyoxal cross-linking processes|
|US4178361||1 Dec 1975||11 Dec 1979||Union Corporation||Sustained release pharmaceutical composition|
|US4582865 *||6 Dec 1984||15 Apr 1986||Biomatrix, Inc.||Cross-linked gels of hyaluronic acid and products containing such gels|
|US4605691||18 Jul 1985||12 Aug 1986||Biomatrix, Inc.||Cross-linked gels of hyaluronic acid and products containing such gels|
|US4636524||8 Mar 1985||13 Jan 1987||Biomatrix, Inc.||Cross-linked gels of hyaluronic acid and products containing such gels|
|US4713448||12 Mar 1985||15 Dec 1987||Biomatrix, Inc.||Chemically modified hyaluronic acid preparation and method of recovery thereof from animal tissues|
|US4716154||7 Jun 1985||29 Dec 1987||Pharmacia Ab||Gel of crosslinked hyaluronic acid for use as a vitreous humor substitute|
|US4937270||18 Sep 1987||26 Jun 1990||Genzyme Corporation||Water insoluble derivatives of hyaluronic acid|
|US5017229 *||25 Jun 1990||21 May 1991||Genzyme Corporation||Water insoluble derivatives of hyaluronic acid|
|US5099013||16 Nov 1990||24 Mar 1992||Biomatrix, Inc,||Hylan preparation and method of recovery thereof from animal tissues|
|US5128326||23 Jul 1990||7 Jul 1992||Biomatrix, Inc.||Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same|
|US5143724||9 Jul 1990||1 Sep 1992||Biomatrix, Inc.||Biocompatible viscoelastic gel slurries, their preparation and use|
|US5219360||10 May 1991||15 Jun 1993||Fortis Research Corporation||Mammary prosthesis fill and method of making same|
|US5246698||20 Dec 1991||21 Sep 1993||Biomatrix, Inc.||Biocompatible viscoelastic gel slurries, their preparation and use|
|US5399351||24 Jun 1993||21 Mar 1995||Biomatrix, Inc.||Biocompatible viscoelastic gel slurries, their preparation and use|
|US5527893||23 Dec 1992||18 Jun 1996||Genzyme Corporation||Water insoluble derivatives of polyanionic polysaccharides|
|US5676694||7 Jun 1996||14 Oct 1997||Medtronic, Inc.||Medical electrical lead|
|US5760200||25 Jan 1995||2 Jun 1998||Genzyme Corporation||Water insoluble derivatives of polyanionic polysaccharides|
|US5783691||26 Apr 1996||21 Jul 1998||Biomatrix, Inc.||Crosslinked hyaluronate gels, their use and method for producing them|
|US6030958||18 Aug 1997||29 Feb 2000||Genzyme Corporation||Water insoluble derivatives of hyaluronic acid|
|US6066325 *||27 Feb 1998||23 May 2000||Fusion Medical Technologies, Inc.||Fragmented polymeric compositions and methods for their use|
|US6086907||29 Aug 1991||11 Jul 2000||University Of Florida Research Foundation, Inc.||Method and composition for preventing surgical adhesions|
|US6174999 *||11 Feb 1992||16 Jan 2001||Genzyme Corporation||Water insoluble derivatives of polyanionic polysaccharides|
|US6235726||18 Aug 1999||22 May 2001||Genzyme Corporation||Water insoluble derivatives of polyanionic polysaccharides|
|US6294202||6 Oct 1994||25 Sep 2001||Genzyme Corporation||Compositions containing polyanionic polysaccharides and hydrophobic bioabsorbable polymers|
|EP0224987A2||5 Aug 1986||10 Jun 1987||Biomatrix, Inc.||Drug delivery systems based on hyaluronan, derivatives thereof and their salts and method of producing same|
|EP0732110A1||16 Feb 1996||18 Sep 1996||Collagen Corporation||Anti-adhesion films and compositions for medical use|
|EP0939086A1 *||27 Feb 1998||1 Sep 1999||Stichting Hyppomedics||Process for producing crosslinked hyaluronic acid|
|GB2151244A||Title not available|
|WO1986000079A1||7 Jun 1985||3 Jan 1986||Pharmacia Ab||Gel of crosslinked hyaluronic acid for use as a vitreous humor substitute|
|WO1986000912A1||16 Jul 1985||13 Feb 1986||Pharmacia Ab||Gel for preventing adhesion between body tissues and process for its production|
|WO1986004355A1||16 Jan 1986||31 Jul 1986||Bio Technology General Corp||Method of producing high molecular weight sodium hyaluronate by fermentation of streptococcus|
|1||Burns, J., et al., Preclinical Evaluation of Seprafilm (TM) Bioresorbable Membrane, Eur. J. Surg., Suppl. 577: 40-48 (1997).|
|2||Burns, J., et al., Preclinical Evaluation of Seprafilm ™ Bioresorbable Membrane, Eur. J. Surg., Suppl. 577: 40-48 (1997).|
|3||Danishefsky et al., Conversion of Carboxyl Groups of Mucopolysaccharides Into Amides of Amino Acid Esters, Carbohydrate Research, vol. 16, pp. 199-205 (1971).|
|4||Larsen, N. E., et al., "Hylan Gel Biomaterial: Dermal and Immunologic Compatibility", J. Biomedical Materials Research, 27: 1129-1134 (1993).|
|5||Sparer et al., Controlled Release from Glycosaminoglycan Drug Complexes, Controlled Release Delivery Systems, Chapter 6, pp. 107-119 (1983).|
|6||*||US 5,808,050, 9/1998, Mares-Guia (withdrawn)*|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US7455248||17 Mar 2005||25 Nov 2008||Genzyme Corporation||Powder delivery device|
|US7578834||3 May 2005||25 Aug 2009||Abdou M S||Devices and methods for the preservation of spinal prosthesis function|
|US7700819||25 Jan 2007||20 Apr 2010||Kci Licensing, Inc.||Biocompatible wound dressing|
|US7758654||20 May 2004||20 Jul 2010||Kensey Nash Corporation||Anti-adhesion device|
|US7763769||21 Apr 2006||27 Jul 2010||Kci Licensing, Inc.||Biocompatible wound dressing|
|US7981871||6 Dec 2004||19 Jul 2011||University Of Utah Research Foundation||Modified macromolescules and associated methods of synthesis and use|
|US8017157||12 Dec 2006||13 Sep 2011||Osiris Therapeutics, Inc.||Method of treating a wound with acidified plasma or serum|
|US8084664||30 Jun 2010||27 Dec 2011||Kci Licensing, Inc.||Biocompatible wound dressing|
|US8124120 *||22 Dec 2003||28 Feb 2012||Anika Therapeutics, Inc.||Crosslinked hyaluronic acid compositions for tissue augmentation|
|US8163974||12 Apr 2010||24 Apr 2012||Kci Licensing, Inc.||Biocompatible wound dressing|
|US8273725||10 Sep 2009||25 Sep 2012||Genzyme Corporation||Stable hyaluronan/steroid formulation|
|US8318695||23 Jul 2008||27 Nov 2012||Allergan, Inc.||Tunably crosslinked polysaccharide compositions|
|US8338375||29 Dec 2009||25 Dec 2012||Allergan, Inc.||Packaged product|
|US8338388||18 May 2010||25 Dec 2012||Allergan, Inc.||Cross-linking of low-molecular weight and high-molecular weight polysaccharides, preparation of injectable monophase hydrogels, polysaccharides and hydrogels obtained|
|US8357795 *||26 Feb 2009||22 Jan 2013||Allergan, Inc.||Hyaluronic acid-based gels including lidocaine|
|US8361164||19 Jul 2010||29 Jan 2013||Kensey Nash Corporation||Anti-adhesion device|
|US8394782||21 Nov 2008||12 Mar 2013||Allergan, Inc.||Polysaccharide gel formulation having increased longevity|
|US8394783||4 Apr 2012||12 Mar 2013||Allergan, Inc.||Polysaccharide gel formulation having multi-stage bioactive agent delivery|
|US8394784||10 Nov 2009||12 Mar 2013||Allergan, Inc.||Polysaccharide gel formulation having multi-stage bioactive agent delivery|
|US8414907||28 Apr 2005||9 Apr 2013||Warsaw Orthopedic, Inc.||Coatings on medical implants to guide soft tissue healing|
|US8513216||11 Sep 2009||20 Aug 2013||Allergan, Inc.||Polysaccharide gel formulation having increased longevity|
|US8524213||26 Jun 2006||3 Sep 2013||Genzyme Corporation||Polymeric materials, their preparation and use|
|US8563532||3 Aug 2012||22 Oct 2013||Allergan Industrie Sas||Cross-linking of low-molecular weight and high-molecular weight polysaccharides, preparation of injectable monophase hydrogels, polysaccharides and hydrogels obtained|
|US8586562||10 May 2010||19 Nov 2013||Allergan Industrie, Sas||Fluid compositions for improving skin conditions|
|US8658148||19 Jun 2008||25 Feb 2014||Genzyme Corporation||Chemically modified dendrimers|
|US8668863||26 Feb 2009||11 Mar 2014||Board Of Regents, The University Of Texas System||Dendritic macroporous hydrogels prepared by crystal templating|
|US8680073||23 Aug 2012||25 Mar 2014||Genzyme Corporation||Stable hyaluronan/steroid formulation|
|US8691279||21 Mar 2011||8 Apr 2014||Allergan, Inc.||Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation|
|US8691793||15 Jul 2011||8 Apr 2014||University Of Utah Research Foundation||Modified macromolecules and associated methods of synthesis and use|
|US8697044||7 Oct 2008||15 Apr 2014||Allergan, Inc.||Crossed-linked hyaluronic acid and collagen and uses thereof|
|US8697057||16 Feb 2012||15 Apr 2014||Allergan, Inc.||Compositions and soft tissue replacement methods|
|US8703118||8 Mar 2012||22 Apr 2014||Allergan, Inc.||Crossed-linked hyaluronic acid and collagen and uses thereof|
|US8728499||4 Jun 2013||20 May 2014||Board Of Regents, The University Of Texas System||Dendritic macroporous hydrogels prepared by crystal templating|
|US8735644||20 Dec 2011||27 May 2014||Kci Licensing, Inc.||Biocompatible wound dressing|
|US8747870||16 Jan 2013||10 Jun 2014||University Of Utah Research Foundation||Polymeric compositions and methods of making and using thereof|
|US8822676||13 Mar 2012||2 Sep 2014||Allergan Industrie, Sas||Hyaluronic acid-based gels including lidocaine|
|US8853184||27 Mar 2013||7 Oct 2014||Allergan, Inc.||Polysaccharide gel formulation having increased longevity|
|US8883139||16 Feb 2012||11 Nov 2014||Allergan Inc.||Compositions and soft tissue replacement methods|
|US8889123||16 Feb 2012||18 Nov 2014||Allergan, Inc.||Compositions and soft tissue replacement methods|
|US8921338||12 Nov 2013||30 Dec 2014||Allergan Industrie, Sas||Fluid compositions for improving skin conditions|
|US8932622||1 Jun 2009||13 Jan 2015||Actamax Surgical Materials, Llc||Tissue coating for preventing undesired tissue-to-tissue adhesions|
|US8946192||24 May 2012||3 Feb 2015||Allergan, Inc.||Heat stable hyaluronic acid compositions for dermatological use|
|US8946194||7 Oct 2011||3 Feb 2015||Board Of Regents, University Of Texas System||One-step processing of hydrogels for mechanically robust and chemically desired features|
|US9005605||16 Feb 2012||14 Apr 2015||Allergan, Inc.||Compositions and soft tissue replacement methods|
|US9012517||19 Mar 2014||21 Apr 2015||Allergan, Inc.||Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation|
|US9062130||12 Sep 2013||23 Jun 2015||Allergan Industrie Sas||Cross-linking of low-molecular weight and high-molecular weight polysaccharides, preparation of injectable monophase hydrogels, polysaccharides and hydrogels obtained|
|US9089517||16 Oct 2012||28 Jul 2015||Allergan Industrie Sas||Hyaluronic acid-based gels including lidocaine|
|US9089518||16 Oct 2012||28 Jul 2015||Allergan Industrie Sas||Hyaluronic acid-based gels including lidocaine|
|US9089519||1 Apr 2014||28 Jul 2015||Allergan Industrie Sas||Hyaluronic acid-based gels including lidocaine|
|US9095558||7 Oct 2011||4 Aug 2015||Board Of Regents, The University Of Texas System||Anti-adhesive barrier membrane using alginate and hyaluronic acid for biomedical applications|
|US9114188||13 Jan 2012||25 Aug 2015||Allergan, Industrie, S.A.S.||Stable hydrogel compositions including additives|
|US9119901||28 Apr 2005||1 Sep 2015||Warsaw Orthopedic, Inc.||Surface treatments for promoting selective tissue attachment to medical impants|
|US9125840||12 Nov 2013||8 Sep 2015||Allergan Industrie Sas||Methods for improving skin conditions|
|US20050136122 *||22 Dec 2003||23 Jun 2005||Anika Therapeutics, Inc.||Crosslinked hyaluronic acid compositions for tissue augmentation|
|US20050205087 *||17 Mar 2005||22 Sep 2005||Genzyme Corporation||Powder delivery device|
|US20050220721 *||17 Mar 2005||6 Oct 2005||Kablik J J||Anti-adhesion spraying|
|US20050273120 *||3 May 2005||8 Dec 2005||Abdou M S||Devices and methods for the preservation of spinal prosthesis function|
|US20060189910 *||21 Apr 2006||24 Aug 2006||Kci Licensing, Inc.||Biocompatible wound dressing|
|US20100028438 *||26 Feb 2009||4 Feb 2010||Lebreton Pierre F||Hyaluronic Acid-Based Gels Including Lidocaine|
|CN100537606C||30 Dec 2004||9 Sep 2009||建新公司||Cohesive gels form cross-linked hyaluronan and/or HYLAN, their preparation and use|
|CN101068555B||17 Mar 2005||6 Jul 2011||根茨美公司||Anti-adhesion spraying|
|EP2289523A2||20 Dec 2005||2 Mar 2011||Genzyme Corporation||Regimens for intra-articular viscosupplementation|
|EP2399940A2||21 Apr 2011||28 Dec 2011||University of Utah Research Foundation||Modified macromolecules and methods of making and using thereof|
|EP2664334A1||20 Dec 2005||20 Nov 2013||Genzyme Corporation||Regimens for intra-articular viscosupplementation|
|EP2664335A2||20 Dec 2005||20 Nov 2013||Genzyme Corporation||Regimens for intra-articular viscosupplementation|
|EP2664336A2||20 Dec 2005||20 Nov 2013||Genzyme Corporation||Regimens for intra-articular viscosupplementation|
|WO2005066215A1 *||30 Dec 2004||21 Jul 2005||Genzyme Corp||Cohesive gels form cross-linked hyaluronan and/or hylan, their preparation and use|
|WO2005089472A2 *||17 Mar 2005||29 Sep 2005||Jude M Colt||Anti-adhesion spraying|
|WO2006073835A2||20 Dec 2005||13 Jul 2006||Genzyme Corp||Regiments for intra-articular viscosupplementation|
|U.S. Classification||424/78.08, 424/422, 514/781, 424/400, 424/423|
|International Classification||C08B37/08, A61L31/00, A61K47/36, C08B31/00, C08B11/20, C08B15/00, A61L31/04|
|Cooperative Classification||C08B15/005, C08B11/20, A61K47/36, C08B31/006, A61L31/042, C08B37/0072|
|European Classification||A61L31/04D, C08B11/20, A61K47/36, C08B37/00P2F, C08B15/00B, C08B31/00B2|
|12 Jun 2000||AS||Assignment|
|18 Aug 2006||FPAY||Fee payment|
Year of fee payment: 4
|18 Aug 2010||FPAY||Fee payment|
Year of fee payment: 8
|23 Jul 2014||FPAY||Fee payment|
Year of fee payment: 12